BIOCHEMICAL TOXICOLOGY AND MOLECULAR STRESS RESPONSES

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Environmental chemicals have pleotropic toxic effects on humans and other organisms including organ failure, birth defects and cancers, which are elicited by a complex pattern of molecular and biochemical signals. Given the thousands of environmental toxins, it can be difficult to determine a mechanism of action or to identify -causative agents for these responses. However, it is clear that the biological consequences are due to the interaction of the toxin, or a metabolite, with components of the cell. Although there are many targets for toxins in a cell, damage to many different targets may elicit common biochemical mechanisms of toxicity, e.g. altered Ca2+ homeostasis, depletion of glutathione and oxidative stress, which couple the damage to cell death. Therefore, the pleotropic responses to chemical toxins may be linked by a smaller number of biochemical events. A change in gene expression is a common response to environmental toxins, and may serve to regulate early events which lead to the pleotropic biological responses. The most common genes which are activated by chemical toxins are stress response genes such as heat shock proteins, glucose regulated proteins and transcription activating factors. It is possible that these molecular stress responses are involved either in development of toxicities, or protection. Our long term goal is to determine if changes in stress gene expression represent common points of regulation for the biological response to,toxins. The specific hypothesis to be tested is, "The signals for increased expression of stress responsive genes overlap with the signals which mediate cytotoxicity for different classes of chemical toxins." We will use a well characterized cell model of toxicity, LLC-PK1 cells, and three different toxins, iodoacetamide, t-butylhydroperoxide and nephrotoxic cysteine conjugates, to test this hypothesis. Mechanisms for activation of 3 stress responsive genes (hsp7O, grp78 and gadd153) by all three toxins will be compared to determine if common transcriptional and posttranscriptional signalling mechanisms exist. We will also begin studies to determine the genomic basis for differences in resistance to toxins. Our hope is that elucidating these fundamental molecular responses will allow us to better understand the cascade of events which result in the biological response to chemical toxins.